Inhibition of neutral sphingomyelinase-2 facilitates remyelination

Seung Wan Yoo; Amit Agarwal; Matthew D. Smith; Saja S. Khuder; Emily G. Baxi; Ajit G. Thomas; Camilo Rojas; Mohammed Moniruzzman; Barbara S. Slusher; Dwight E. Bergles; Peter A. Calabresi; Norman J. Haughey

doi:10.1101/686287

Inhibition of neutral sphingomyelinase-2 facilitates remyelination

Seung Wan Yoo, Amit Agarwal, Matthew D. Smith, Saja S. Khuder, Emily G. Baxi, Ajit G. Thomas, Camilo Rojas, Mohammed Moniruzzman, Barbara S. Slusher, Dwight E. Bergles, Peter A. Calabresi, Norman J. Haughey

School of Medicine

Research output: Contribution to journal › Article › peer-review

Abstract

For reasons that are not completely understood, remyelination is often incomplete, producing thin myelin sheaths with disorganized structure. We investigated the cellular basis for this altered myelin structure, and found that the response of oligodendrocyte progenitor cells (OPCs), and mature oligodendrocytes to TNFα and IL-1β is modified by the expression of the sphingomyelin hydrolase nSMase2. OPCs do not express nSMase2, and exhibit a protective response to these cytokines manifest by decreased ceramide, increased sphingosine 1-phosphate, and increased cell motility. Mature oligodendrocytes express nSMase2, and respond to TNFα and IL-1β with a stress phenotype, evidenced by increased ceramide, decreased sphingosine, and active caspase 3. Pharmacological inhibition or a targeted genetic deletion of nSMase2 in vivo increased myelin thickness, and enhanced myelin compaction. These results suggest that inhibition of nSMase2 improves the quality of new myelin by protecting maturing/myelinating oligodendrocytes. Pharmacological inhibition of nSMase2 following a demyelinating event could stabilize the structure of these newly formed myelin sheaths and protect them from secondary demyelination.

Original language	English (US)
Journal	Unknown Journal
DOIs	https://doi.org/10.1101/686287
State	Published - Jun 28 2019

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)
Agricultural and Biological Sciences(all)
Immunology and Microbiology(all)
Neuroscience(all)
Pharmacology, Toxicology and Pharmaceutics(all)

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Inhibition of neutral sphingomyelinase-2 facilitates remyelination. / Yoo, Seung Wan; Agarwal, Amit; Smith, Matthew D.; Khuder, Saja S.; Baxi, Emily G.; Thomas, Ajit G.; Rojas, Camilo; Moniruzzman, Mohammed; Slusher, Barbara S.; Bergles, Dwight E.; Calabresi, Peter A.; Haughey, Norman J.

In: Unknown Journal, 28.06.2019.

Research output: Contribution to journal › Article › peer-review

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title = "Inhibition of neutral sphingomyelinase-2 facilitates remyelination",

abstract = "For reasons that are not completely understood, remyelination is often incomplete, producing thin myelin sheaths with disorganized structure. We investigated the cellular basis for this altered myelin structure, and found that the response of oligodendrocyte progenitor cells (OPCs), and mature oligodendrocytes to TNFα and IL-1β is modified by the expression of the sphingomyelin hydrolase nSMase2. OPCs do not express nSMase2, and exhibit a protective response to these cytokines manifest by decreased ceramide, increased sphingosine 1-phosphate, and increased cell motility. Mature oligodendrocytes express nSMase2, and respond to TNFα and IL-1β with a stress phenotype, evidenced by increased ceramide, decreased sphingosine, and active caspase 3. Pharmacological inhibition or a targeted genetic deletion of nSMase2 in vivo increased myelin thickness, and enhanced myelin compaction. These results suggest that inhibition of nSMase2 improves the quality of new myelin by protecting maturing/myelinating oligodendrocytes. Pharmacological inhibition of nSMase2 following a demyelinating event could stabilize the structure of these newly formed myelin sheaths and protect them from secondary demyelination.",

author = "Yoo, {Seung Wan} and Amit Agarwal and Smith, {Matthew D.} and Khuder, {Saja S.} and Baxi, {Emily G.} and Thomas, {Ajit G.} and Camilo Rojas and Mohammed Moniruzzman and Slusher, {Barbara S.} and Bergles, {Dwight E.} and Calabresi, {Peter A.} and Haughey, {Norman J.}",

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AU - Agarwal, Amit

AU - Smith, Matthew D.

AU - Khuder, Saja S.

AU - Baxi, Emily G.

AU - Thomas, Ajit G.

AU - Rojas, Camilo

AU - Moniruzzman, Mohammed

AU - Slusher, Barbara S.

AU - Bergles, Dwight E.

AU - Calabresi, Peter A.

AU - Haughey, Norman J.

N1 - Publisher Copyright: The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license. Copyright: Copyright 2020 Elsevier B.V., All rights reserved.

PY - 2019/6/28

Y1 - 2019/6/28

N2 - For reasons that are not completely understood, remyelination is often incomplete, producing thin myelin sheaths with disorganized structure. We investigated the cellular basis for this altered myelin structure, and found that the response of oligodendrocyte progenitor cells (OPCs), and mature oligodendrocytes to TNFα and IL-1β is modified by the expression of the sphingomyelin hydrolase nSMase2. OPCs do not express nSMase2, and exhibit a protective response to these cytokines manifest by decreased ceramide, increased sphingosine 1-phosphate, and increased cell motility. Mature oligodendrocytes express nSMase2, and respond to TNFα and IL-1β with a stress phenotype, evidenced by increased ceramide, decreased sphingosine, and active caspase 3. Pharmacological inhibition or a targeted genetic deletion of nSMase2 in vivo increased myelin thickness, and enhanced myelin compaction. These results suggest that inhibition of nSMase2 improves the quality of new myelin by protecting maturing/myelinating oligodendrocytes. Pharmacological inhibition of nSMase2 following a demyelinating event could stabilize the structure of these newly formed myelin sheaths and protect them from secondary demyelination.

AB - For reasons that are not completely understood, remyelination is often incomplete, producing thin myelin sheaths with disorganized structure. We investigated the cellular basis for this altered myelin structure, and found that the response of oligodendrocyte progenitor cells (OPCs), and mature oligodendrocytes to TNFα and IL-1β is modified by the expression of the sphingomyelin hydrolase nSMase2. OPCs do not express nSMase2, and exhibit a protective response to these cytokines manifest by decreased ceramide, increased sphingosine 1-phosphate, and increased cell motility. Mature oligodendrocytes express nSMase2, and respond to TNFα and IL-1β with a stress phenotype, evidenced by increased ceramide, decreased sphingosine, and active caspase 3. Pharmacological inhibition or a targeted genetic deletion of nSMase2 in vivo increased myelin thickness, and enhanced myelin compaction. These results suggest that inhibition of nSMase2 improves the quality of new myelin by protecting maturing/myelinating oligodendrocytes. Pharmacological inhibition of nSMase2 following a demyelinating event could stabilize the structure of these newly formed myelin sheaths and protect them from secondary demyelination.

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